Radio-opaque polymeric biomaterials

ABSTRACT

Iodinated and/or brominated derivatives of aromatic dihydroxy monomers are prepared and polymerized to form radio-opaque polymers. The monomers may also be copolymerized with other dihydroxy monomers. The iodinated and brominated aromatic dihydroxy monomers can be employed as radio-opacifying, biocompatible non-toxic additives for other polymeric biomaterials. Radio-opaque medical implants and drug delivery devices for implantation prepared from the polymers of the present invention are also disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.10/691,750, which was filed on Oct. 23, 2003, which application, inturn, is a continuation of U.S. patent application Ser. No.10/288,076,which was filed on Nov. 5, 2002 with the United States Patent andTrademark Office, which application, in turn, is a Divisional of U.S.patent application Ser. No. 09/554,027 filed Jul. 3, 2000 which issuedas U.S. Pat. No. 6,475,477 on Nov. 5, 2002, and which claims prioritybenefit under 35 U.S.C. §371 of PCT/US98/23777 filed Nov. 6, 1998,which, in turn, claims priority benefit of U.S. Provisional PatentApplication No.60/064,905, filed on Nov. 7, 1997. The disclosures of theaforementioned applications are incorporated herein by reference.

GOVERNMENT LICENSE RIGHTS

The U.S. Government has a paid-up license in this invention and theright in limited circumstances to require the patent owner to licenseothers on reasonable terms as required by the terms of Grant Nos.GM-39455 and GM-49849 awarded by the National Institutes of Health.

TECHNICAL FIELD

The present invention relates to radio-opaque biodegradablepolycarbonates and polyarylates and the block copolymers thereof withpoly(alkylene oxides). In particular, the present invention relates topolycarbonates and polyarylates and the poly(alkylene oxide) blockcopolymers thereof that are radio-opaque as a consequence of beinghomopolymers and copolymers of dihydroxy monomers having iodinated orbrominated aromatic rings as part of their structure.

BACKGROUND OF THE INVENTION

Diphenols are monomeric starting materials for polycarbonates,polyiminocarbonates, polyarylates, polyurethanes, and the like. Commonlyowned U.S. Pat. Nos. 5,099,060 and 5,198,507 disclose amino acid-deriveddiphenol compounds, useful in the polymerization of polycarbonates andpolyiminocarbonates. The resulting polymers are useful as degradablepolymers in general and as tissue-compatible bioerodible materials formedical uses, in particular. The suitability of these polymers for theirend use application is the result of their polymerization from diphenolsderived from the naturally occurring amino acid, L-tyrosine. Thedisclosures of U.S. Pat. Nos. 5,099,060 and 5,198,507 are herebyincorporated by reference. These previously-known polymers are strong,water-insoluble materials that can best be used as structural implants.

The same monomeric L-tyrosine derived diphenols are also used in thesynthesis of polyarylates as described in commonly owned U.S. Pat. No.5,216,115 and in the synthesis of poly(alkylene oxide) block copolymerswith the aforementioned polycarbonates and polyarylates, which isdisclosed in commonly owned U.S. Pat. No. 5,658,995. The disclosures ofU.S. Pat. Nos. 5,216,115 and 5,658,995 are also hereby incorporated byreference.

Commonly owned International Application No. WO 98/36013 disclosesdihydroxy monomers prepared from α-, β- and hydroxy acids andderivatives of L-tyrosine that are also useful starting materials in thepolymerization of polycarbonates, polyiminocarbonates, polyarylates, andthe like. The preparation of polycarbonates, polyarylates andpolyiminocarbonates from these monomers is also disclosed. Thedisclosure of International Application No. WO 98/36013 is also herebyincorporated by reference.

Synthetic, degradable polymers are currently being evaluated as medicalimplants in a wide range of applications, such as orthopedic bonefixation devices, drug delivery systems, cardiovascular implants, andscaffolds for the regeneration/engineering of tissue. Such polymers,when used as implants, are non-traceable without invasive procedures. Aradio-opaque polymer would offer the unique advantage of being traceablevia routine X-ray imaging. The fate of such an implant through variousstages of its utility could be followed without requiring invasivesurgery.

Davy et al., J. Dentist., 10(3), 254-64 (1982), disclose brominatedderivatives of poly(methyl methacrylate) that are radio-opaque.Copolymerization with non-brominated analogs was required to obtain thethermomechanical properties required for its desired use as a denturebase. Only in a small range of certain percentage concentrations of thebromo-derivative does the material exhibit acceptable thermomechanicalproperties. In addition, there is no disclosure that the materialsexhibiting acceptable properties remain biocompatible following theaddition of bromine to the polymer structure. In contrast to thepolymers disclosed in this application, the brominated poly(methylmethacrylates) do not degrade. However, because the bromine atoms arelocated on the aliphatic ester side chain, upon side chain estercleavage, the polymer loses its radio-opacity.

Horak et al., Biomater. 8, 142-5(1987), disclose the triiodobenzoic acidester of poly(2-hydroxyethyl methacrylate) to be useful as aradio-opaque X-ray imaging marker compound. The iodine content wasreported to affect the contrast, volume, mechanical properties andhydrophobicity of the polymer. A proper balance of properties, includingradio-contrast and swellability, was achieved through optimization ofthe iodine content. Again, this material does not degrade through themain chain and loses radio-opacity upon side chain ester cleavagebecause the iodine atoms are located on the ester side chain.

Cabasso et al., J. Appl. Polym. Sci. 38, 1653-66 (1989), disclose thepreparation of a radio-opaque miscible polymer coordination complex ofpoly(methyl methacrylate) and a uranium salt, uranyl nitrate. Thepolymer does not degrade through the main chain and the biocompatibilityof the uranyl nitrate complex is not reported, nor has the long-termstability of the complex in vivo been established.

Cabasso et al., J. Appl. Polym. Sci., 41 3025-42 (1990), discloses thepreparation of radio-opaque coordination complexes of bismuth bromideand uranyl hexahydrate with polymers prepared from acrylated phosphorylesters containing 1,3-dioxalane moieties derived from polyols such asglycerol, D-mannitol, D-sorbitol, pentaerythritol and dipentaerythritol.The phosphoryl group was selected to provide stronger coordinating sitesfor the bismuth and uranium salts and to impart adhesive propertiestoward hard tissues. Preliminary biocompatibility data indicatedsatisfactory performance, but the polymer does not degrade through themain chain and the long-term stability of the complex in vivo is notreported.

Jayakrishnan et al., J. Appl. Polym. Sci., 44, 743-8 (1992), disclosesradio-opaque polymers of triiodophenyl methacrylate and of theiothalamic ester of 2-hydroxyethyl methacrylate. Polymers of usefulmolecular weight were not obtained, attributable to the presence ofbulky iodine atoms in the monomer side chain. It was possible to obtaincopolymers with non-iodinated analogs in the presence of crosslinkingagents, such that up to 25% of the iodinated monomer could beincorporated. Preliminary biocompatibility data indicated that thepresence of triiodophenyl methacrylate caused blood hemolysis. Inaddition, the materials also do not degrade through the main chain, andin the event of side chain ester cleavage, would lose theirradio-opacity because of the iodine atoms being located in the sidechain.

Kraft et al., Biomater., 18, 31-36 (1997), discloses the preparation ofradio-opaque iodine-containing poly(methyl methacrylates). The monomerswere ortho- and para-iodo and 2,3,5-triiodobenzoic acid esters of2-hydroxymethyl methacrylate, and the para-iodophenol ester of methylmethacrylic acid. The monomers were copolymerized with one or morenon-iodinated analogs and a small amount of crosslinkers to producepolymer hydrogels with varying iodine contents. It was reported that thehydrogels were well tolerated by subcutaneous tissues and that thepresence of iodine did not severely alter the swellability of thehydrogel. No tissue necrosis, abscess formation or acute inflammationwas observed, although all implants were surrounded by a fibrouscapsule. However, these materials also do not degrade through the mainpolymer chain, and upon side chain ester cleavage, lose radio-opacitybecause of the iodine atoms being located in the ester side chain.

Currently, no technology is available to provide radio-opaque polymersthat degrade through the main polymer chain, such as the above-discussedtyrosine-derived polymers. For their intended use as medical implants,radio-opaqueness is a valuable property. A need exists for radio-opaquepolymers that degrade through the main polymer chains, such as thetyrosine-derived polymers discussed above.

SUMMARY OF THE INVENTION

These needs are met by the present invention. It has now been found thatiodination or bromination of the aromatic rings of dihydroxy monomersrenders the resulting polymers radio-opaque. Significantly, theresulting polymers exhibit good mechanical and engineering propertieswhile degrading into relatively non-toxic products after implantation invivo.

In general, the ability of a species to absorb X-rays is relateddirectly to atomic number and is approximated by the relationship.m=kl ³ Z ⁴+0.2wherein m is the absorption coefficient, l is the wavelength of theincident X-ray, Z is the atomic number of the absorbing species and k isthe proportionality constant. Iodine and bromine atoms, because of theirhigh mass, scatter X-rays and impart radio-opaqueness. This is highlysignificant and allows clinicians to visualize any implanted deviceprepared from a radio-opaque polymer by simple X-ray imaging.

Thus, iodinated and/or brominated derivatives of dihydroxy monomers maybe prepared and polymerized to form radio-opaque polycarbonates andpolyarylates. These monomers may also be copolymerized withpoly(alkylene oxides) and other dihydroxy monomers. In addition, theiodinated and brominated dihydroxy monomers can be employed asradio-opacifying, biocompatible non-toxic additives for other polymericbiomaterials.

Therefore, according to one aspect of the present invention, adiphenolic radio-opacifying, biocompatible, non-toxic additive forpolymeric biomaterials is provided having the structure of Formula I:

Formula I represents a diphenol compound substituted with at least onebromine or iodine atom, wherein each X₁ and X₂ is independently aniodine or bromine atom, Y1 and Y2 are independently between zero andtwo, inclusive, and R₉ is an alkyl, aryl or alkylaryl group with up to18 carbon atoms. Preferably, R₉ contains as part of its structure acarboxylic acid group or a carboxylic acid ester group, wherein theester is selected from straight and branched alkyl and alkylaryl groupscontaining up to 18 carbon atoms in addition to the rest of the R₉structure, and ester derivatives of biologically and pharmaceuticallyactive compounds covalently bonded to the diphenol, which are also notincluded among the carbons of R₉. R₉ can also contain non-carbon atomssuch as iodine, bromine, nitrogen and oxygen.

In particular, R₉ can have a structure related to derivatives of thenatural amino acid tyrosine, cinnamic acid, or 3-(4-hydroxyphenyl)propionic acid. In these cases, Rg assumes the specific structure shownin Formula II:

R₀ is selected from (—CH═CH—), (—CHJ₁-CHJ₂-) and (—CH₂—)_(d) and R₄ isselected from (—CH═CH—), (—CHJ₁—CHJ₂-) and (—CH₂—)_(a), in which a and dare independently 0 to 8, inclusive, and J₁ and J₂ are independently Bror I. Z is H, a free carboxylic acid group, or an ester or amide thereofZ preferably is a pendent group having a structure according to FormulaIV:

wherein L is selected from hydrogen and straight and branched alkyl andalkylaryl groups containing up to 18 carbon atoms and derivatives ofbiologically and pharmaceutically active compounds covalently bonded tothe dihydroxy compound.

Z can also be a pendent group having a structure according to FormulaIVa:

wherein M is selected from —OH, —NH—NH₂, —O—R₁₀—NH₂, —O—R₁₀—OH,—NH—R₁₀—NH₂, —NH—R₁₀—OH,

a C-terminus protecting group and a derivative of a biologically orpharmaceutically active compound covalently bonded to the pendentfunctional group by means of amide bond, wherein in the underivatizedbiologically of pharmaceutically active compound a primary or secondaryamine is present in the position of the amide bond in the derivative.

Z can also be a pendent group having a structure represented by FormulaIVb:

wherein M is a derivative of a biologically or pharmaceutically activecompound covalently bonded to the pendent functional group by means ofR₃, wherein R₃ is a linkage selected from —NH—NH— in the case when inthe underivatized biologically or pharmaceutically active compound analdehyde or ketone is present at the position links to the pendentfunctional groups by means of R₃; and —NH—NH—, —NH—R₁₀—NH—, —O—R₁₀—NH—,—O—R₁₀—O— or —NH—R₁₀—O— in the case when in the underivatizedbiologically or pharmaceutically active compound a carboxylic acid ispresent in the position linked to the pendent functional group by meansof R₃; and

in the case when in the underivatized biologically or pharmaceuticallyactive compound a primary or secondary amine or primary hydroxyl ispresent in the position linked to the pendent functional group by meansof R₃.

R₁₀ is selected from alkyl groups containing from 2 to 6 carbon atoms,aromatic groups, α-, β-, γ- and ω-amino acids and peptide sequences.

According to another aspect of the present invention, aradio-opacifying, biocompatible, non-toxic dihydroxy additive forpolymeric biomaterials is provided having the structure of Formula III:

Formula III represents a dihydroxy compound substituted with at leastone bromine or iodine atom and having a structure related to derivativesof tyrosine joined by way of an amide linkage to an α-, β- or γ-hydroxyacid or derivative thereof Each X₂ is independently an iodine or bromineatom; Y2 is 1 or 2; R₅ and R₆ are each independently selected from H,bromine, iodine and straight and branched alkyl groups having up to 18carbon atoms; R₀ is (—CH₂—)_(d), —CH═CH— or (—CHJ₁-CHJ₂-) and R₁₅ is(—CH₂—)_(m), —CH═CH— or (—CHJ₁-CHJ₂-), wherein J₁ and J₂ areindependently Br or I and d and m are independently between 0 and 8,inclusive. Z is the same as described above with respect to Formula II.

According to another aspect of the present invention, radio-opaquebiocompatible polymers are provided having monomeric repeating unitsdefined in Formulae Ia and IIIa:

Formula Ia represents a diphenolic unit wherein X₁, X₂, Y1, Y2 and R₉are the same as described above with respect to Formula I. Formula IIIarepresents an aromatic dihydroxy unit wherein X₂, Y2, R₀, R₅, R₆, R₁₅and Z are the same as described above with respect to Formula III.

Copolymers in accordance with the present invention have a seconddihydroxy unit defined in Formulae Ib or IIIb.

In the diphenolic subunit of Formula Ib, R₁₂ is an alkyl, aryl oralkylaryl group with up to 18 carbon atoms, preferably substituted witha pendent free carboxylic acid group or an ester or amide thereof,wherein the ester or amide is selected from straight and branched alkyland alkylaryl esters containing up to 18 carbon atoms, in addition tothe rest of the R₁₂ structure, and derivatives of biologically andpharmaceutically active compounds covalently bonded to the polymer,which are also not included among the carbons of R₁₂. R₁₂ can alsocontain non-carbon atoms such as nitrogen and oxygen. In particular, R₁₂can have a structure related to derivatives of the natural amino acidtyrosine, cinnamic acid, or 3′(4′-hydroxyphenyl) propionic acid.

For derivatives of tyrosine, 3′(4′-hydroxyphenyl) propionic acid andcinnamic acid, R₁₂ assumes the specific structure shown in Formula II inwhich R_(o) is —CH═CH— or (—CH₂—)_(d) and R₄ is —CH═CH— or (—CH₂—)_(a),in which a and d are independently 0 to 8, inclusive. Z is the same asdescribed above with respect to Formula II.

In the dihydroxy subunit of Formula IIIb, R₁₆ and R₁₇ are eachindependently selected from H or straight or branched alkyl groupshaving up to 18 carbon atoms; R₁₈ is —CH═CH— or (—CH₂—)_(d) and R₁₉ is—CH═CH— or (—CH₂—)_(e), in which d and e are independently between 0 and8, inclusive. Z is again the same as described above with respect toFormula II.

Some polymers of this invention may also contain blocks of poly(alkyleneoxide) as defined in Formula VII. In Formula VII, R₇ is independently analkylene group containing up to 4 carbon atoms and k is between about 5and about 3,000.—(O—R₇)_(k)—O—  (VII)

A linking bond, designated as “A” is defined to be either

wherein R₈ is selected from saturated and unsaturated, substituted andunsubstituted alkyl, aryl and alkylaryl groups containing up to 18carbon atoms. Thus, polymers in accordance with the present inventionhave the structure of Formulae VIII and VIIIa:

In both formulae, f and g are the molar ratios of the various subunits.The range of f and g can be from 0 to 0.99. It is understood that thepresentation of both formulae is schematic and that the polymerstructures represented are true random copolymers where the differentsubunits can occur in any random sequence throughout the polymerbackbone. Formulae VIII and VIIIa provide a general chemical descriptionof polycarbonates when A is

Formulae VIII and VIIIa provide a general description of polyarylateswhen A is

Furthermore, several limiting cases can be discerned: When g=0, thepolymer contains only iodine or bromine-substituted monomeric repeatingunits. If g is any fraction greater than 0 but smaller than 1, acopolymer is obtained that contains a defined ratio of monomericrepeating units substituted with bromine or iodine and monomericrepeating units that are bromine- and iodine-free.

If f=0, the polymer will not contain any poly(alkylene oxide) blocks.The frequency at which poly(alkylene oxide) blocks can be found withinthe polymer backbone increases as the value of f increases.

The radio-opaque bromine- and iodine-substituted dihydroxy compounds ofthe present invention meet the need for biocompatible biodegradableadditives that are miscible with radio-opaque polymeric biomaterials andenhance the radio-opacity of the polymeric materials. Therefore, thepresent invention also includes the radio-opaque bromine- andiodine-substituted dihydroxy compounds of the present invention,physically admixed, embedded in or dispersed in a biocompatiblebiodegradable polymer matrix. Preferably, the dihydroxy compound is ananalogue of a monomeric repeating unit of the matrix polymer.

The bromine- and iodine-containing polymers of the present inventionalso meet the need for radio-opaque processible biocompatiblebiodegradable polymers, the radio-opacity of which is not affected byanything other than degradation of the main polymer chain. Therefore,the present invention also includes implantable medical devicescontaining the radio-opaque polymers of the present invention. Theradio-opaque polymers of the present invention thus find application inareas where both structural solid materials and water-soluble materialsare commonly employed.

Polymers in accordance with the present invention may be prepared havinggood film-forming properties. An important phenomena observed for thepolymers of the present invention having poly(alkylene oxide) segmentsis the temperature dependent face transition of the polymer gel or thepolymer solution in aqueous solvents. As the temperature increases, thegel of the polymers undergo a face transition to a collapsed state,while polymer solutions precipitate at a certain temperature or withincertain temperature ranges. The polymers of the present invention havingpoly(alkylene oxide) segments, and especially those that undergo a phasetransition at about 30° to 40° C. on heating can be used as biomaterialsfor drug release and clinical implantation materials. Specificapplications include films and sheets for the prevention of adhesion andtissue reconstruction.

Therefore, in another embodiment of the present invention, radio-opaquepoly(alkylene oxide) block copolymers of polycarbonates and polyarylatesmay be formed into a sheet or a coating for application to exposedinjured tissues for use as barrier for the prevention of surgicaladhesions as described by Urry et al., Mat. Res. Soc. Symp. Proc., 292,253-64 (1993). Placement of the radio-opaque polymer sheets of thepresent invention may be followed by X-ray imaging without invasivesurgery. This is particularly useful with endoscopic surgery. Therefore,another aspect of the present invention provides a method for preventingthe formation of adhesions between injured tissues by inserting as abarrier between the injured tissues a sheet or a coating of theradio-opaque poly(alkylene oxide) block copolymers of polycarbonates andpolyarylates of the present invention.

The poly(alkylene oxide) segments decrease the surface adhesion of thepolymers of the present invention. As the value of f in Formulae VIIIand VIIIa increases, the surface adhesion decreases. Polymer coatingcontaining poly(alkylene oxide) segments according to the presentinvention may thus be prepared that are resistant to cell attachment anduseful non-thrombogenic coatings on surfaces in contact with blood. Suchpolymers also resist bacterial adhesion in this, and in other medicalapplications as well. The present invention therefore includes bloodcontacting devices and medical implants having surfaces coated with thepolymers of Formulae VIII and VIIIa in which f is greater than 0. Thesurfaces are preferably polymeric surfaces. Methods according to thepresent invention include implanting in the body of the patient ablood-contacting device or medical implant having a surface coated withthe above-described polymers of the present invention containingpoly(alkylene oxide) segments.

Blood contacting or implantable medical devices formed from the polymersof the present invention are also included in the scope of the presentinvention as well. Such polymers may or may not have poly(alkyleneoxide) segments.

The present invention also includes microspheres of the radio-opaquepolymers of the present invention, useful as X-ray contrast agents or asdrug delivery systems, the location of which can be traced by X-rayimaging. For purposes of the present invention, the term “X-ray imaging”is defined as including essentially any imaging technique employingX-rays, including the extensively practiced procedures of radiography,photography and Computerized Axial Tomography Scans (CAT scans). Methodsin accordance with the present invention for the preparation of drugdelivery systems can also be employed in the preparation of radio-opaquemicrospheres for drug delivery.

In another embodiment of the present invention, the polymers arecombined with a quantity of a biologically or pharmaceutically activecompound sufficient for effective site-specific or systemic drugdelivery as described by Gutowska et al., J. Biomater. Res. 29, 811-21(1995), and Hoffman, J. Controlled Release, 6 297-305 (1987). Thebiologically or pharmaceutically active compound may be physicallyadmixed, embedded in or dispersed in the polymer matrix as if it werenot a radio-opaque polymer, eliminating the need for radio-opaque fillermaterials, thereby increasing the drug loading capacity of the matrixpolymer.

Another aspect of the present invention provides a method forsite-specific or systemic drug delivery by implanting in the body of apatient in need thereofan implantable drug delivery device containing atherapeutically effective amount of a biologically or pharmaceuticallyactive compound in combination with a radio-opaque polymer of thepresent invention. As noted above, derivatives of biologically andpharmaceutically active compounds can be attached to the polymerbackbone by covalent bonds, which provides for the sustained release ofthe biologically or pharmaceutically active compound by means ofhydrolysis of the covalent bond with the polymer backbone.

By varying the value of f in the polymers of Formulae VIII and VIIIa,the hydrophilic/hydrophobic ratios of the polymers of the presentinvention can be attenuated to adjust the ability of the polymercoatings to modify cellular behavior. Increasing levels of poly(alkyleneoxide) inhibits cellular attachment, migration and proliferation,increasing the amount of pendent free carboxylic acid group promotescellular attachment, migration and proliferation. Therefore, accordingto yet another aspect of the present invention, a method is provided forregulating cellular attachment, migration and proliferation bycontacting living cells, tissues, or biological fluids containing livingcells with the polymers of the present invention.

A more complete appreciation of the invention and many other intendedadvantages can be readily obtained by reference to the followingdetailed description of the preferred embodiment and claims, whichdisclose the principles of the invention and the best modes which arepresently contemplated for carrying them out.

BEST MODES OF CARRYING OUT THE INVENTION

FIG. 1 is an X-ray image of a radio-opaque polymer pin according to thepresent invention implanted into a section of a rabbit femur.

BEST MODES OF CARRYING OUT THE INVENTION

The present invention provides radio-opaque polycarbonates andpolyarylates, as well as poly(alkylene oxide) block copolymers thereof,in which the radio-opacity is derived from bromine- andiodine-substitution of some or all of the aromatic rings in the polymerbackbone. The bromine- and iodine-substituted polymers are prepared bybrominating or iodinating a pre-monomer compound prior to synthesis ofthe dihydroxy monomer. The dihydroxy monomer is subsequently polymerizedby established procedures, alone, or in combination with dihydroxycompounds that are not bromine- or iodine-substituted.

In particular, the bromine- and iodine-substituted dihydroxy compoundsinclude diphenols having the structure of Formula I wherein R₉ is thesame as described above with respect to Formula I. The diphenolspreferably have the structure of Formula II. Among the preferreddiphenols are compounds in which R₉ has the structure of Formula II inwhich R₄ is —CH₂— or —CHJ₁-CHJ₂- and R₀ is —CH₂— or —CH₂—CH₂—. Mostpreferably, R₄ is —CHJ₁-CHJ₂- and R₀ is —CH₂—. These most preferredcompounds are bromine- and iodine-substituted tyrosine dipeptideanalogues known as desarinotyrosyl-tyrosine, and the alkyl and alkylarylesters thereof. In this preferred group, the diphenols can be regardedas derivatives of tyrosyl-tyrosine dipeptides from which the N-terminalamino group has been removed.

Diphenol compounds that are not bromine- or iodine-substituted have thestructure of Formula Ic:

wherein R₁₂ is the same as described above with respect to Formula Ib.R₁₂ preferably has the structure shown in Formula II in which R_(o) is—CH═CH— or (—CH₂—)_(d) and R₄ is —CH═CH— or (—CH₂—)_(a), in which a andd are independently 0 to 8.

Methods for preparing the diphenol monomers in which R₉ or R₁₂ containas part of their structures a carboxylic acid ester group are disclosedin commonly owned U.S. Pat. Nos. 5,587,507 and 5,670,602, thedisclosures of both of which are hereby incorporated by reference. Thepreferred desarninotyrosyl-tyrosine esters are the ethyl, butyl, hexyl,octyl and benzyl esters. For purposes of the present invention,desaminotyrosyl-tyrosine ethyl ester is referred to as DTE,desaninotyrosyl-tyrosine benzyl ester is referred to as DTBn, and thelike. For purposes of the present invention, the non-esterdesaminotyrosyl-tyrosine free carboxylic acid is referred to as DT.

It is not possible to polymerize the polycarbonates, polyarylates thepoly(alkylene oxide) block copolymers thereof, having pendent freecarboxylic acid groups from corresponding diphenols with pendent freecarboxylic acid groups without cross-reaction of the free carboxylicacid group with the co-monomer. Accordingly, polycarbonates,polyarylates and the poly(alkylene oxide) block copolymers thereof thatare homopolymers or copolymers of benzylester diphenol monomers such asDTBn may be converted to corresponding free carboxylic acid homopolymersand copolymers through the selective removal of the benzyl groups by thepalladium catalyzed hydrogenolysis method disclosed by co-pending andcommonly owned U.S. patent application Ser. No. 09/056,050, filed onApr. 7, 1998. The disclosure of this application is incorporated hereinby reference. The catalytic hydrogenolysis is necessary because theability of the polymer backbone prevents the employment of harsherhydrolysis techniques.

The bromine- and iodine-substituted dihydroxy compounds also include thealiphatic-aromatic dihydroxy compounds having the structure of FormulaIII in which R_(o), R₅, R₁₅, X₂, Y2 and Z are the same as describedabove with respect to Formula III. Among the preferredaliphatic-aromatic dihydroxy compounds are compounds of Formula III inwhich R₁₅ is (—CH₂—)_(m), wherein m is 0, Y2 is 1 and R₅ and R₆ arepreferably independently selected from hydrogen and methyl. Z preferablyhas a structure according to Formula IV in which L is hydrogen or anethyl, butyl, hexyl, octyl or benzyl group. L is more preferablyhydrogen or an ethyl or benzyl group. When R₅ and R₆ are hydrogen, andR₁₅ (—CH₂—)_(m), wherein m=0, the dihydroxy compound is derived fromglycolic acid. When R₁₅ is the same, R₅ is hydrogen and R₆ is methyl,the dihydroxy compound is derived from lactic acid. Dihydroxy compoundsderived from glycolic of lactic acid are particularly preferred.

Aliphatic-aromatic dihydroxy compounds that are not bromine- oriodine-substituted have the structure of Formula IIIc:

wherein R₁₆, R₁₇, R₁₈, R₁₉, and Z are the same as described above withrespect to Formula IIIb. Preferably, R₁₈ (—CH₂—)_(d), in which d is 0and R₁₆ and R₁₇ independently selected from hydrogen and methyl. Mostpreferably, one of R₁₆ and R₁₇ is hydrogen, while the other is methyl.The preferred species of Z are the same as described above with respectto Formula III.

The bromine- and iodine-substituted dihydroxy monomers of the presentinvention are prepared by well-known iodination and brominationtechniques that can be readily employed by those of ordinary skill inthe art without undue experimentation to prepare the monomer compoundsdepicted in Formulae I and III. The substituted phenols from which thedihydroxy monomers of the present invention are prepared undergoortho-directed halogenation. For this reason, meta-iodinated andbrominated dihydroxy monomers are not readily prepared, and triiodo- andtribromophenyl compounds have not been described. Such compounds areintended to be included within the scope of the present invention,should a convenient method for their synthesis be discovered.

Iodine- and bromine-substituted diphenol monomers may be prepared, forexample, by coupling together two phenol compounds in which either orboth of the phenol rings are iodine- or bromine-substituted. Morespecifically, desaninotyrosyl-tyrosine esters may be prepared by themethods described in the above-incorporated U.S. Pat. Nos. 5,587,507 and5,670,602 using desarninotyrosine and tyrosine allyl esters in whicheither or both compounds are bromine- or iodine-substituted. In aparticularly preferred embodiment, desaminotyrosine is mono-iodinated atthe ortho position on the phenolic ring and subsequently coupled with atyrosine alkyl ester to obtain an iodine-substituted diphenol monomer.

Iodine- and bromine-substituted aliphatic-aromatic dihydroxy monomers inaccordance with the present invention are prepared by coupling an α-, β-or γ-hydroxy acid with a phenolic compound in which either or both ofthe hydroxy acid and the diphenol are iodine- or bromine-substituted.For example, a tyrosine alkyl ester is mono-iodinated at the orthoposition on the phenolic ring and subsequently coupled with an α-, β- orγ-hydroxy acid according to the method described in theabove-incorporated International Publication 98/36013 to obtain aniodine-substituted aliphatic-aromatic dihydroxy monomer.

Polycarbonates, polyarylates, poly(alkylene oxide) block copolymersthereof having pendent free carboxylic acid groups also cannot bepolymerized from an aliphatic-aromatic dihydroxy monomer having apendent free carboxylic acid group because of cross-reaction with theco-monomer. Methods for preparing the aliphatic-aromatic dihydroxymonomers of Formulae III and IIIc in which L of Z is not hydrogen aredisclosed in commonly owned International Publication No. 98/36013,thedisclosure of which is hereby incorporated by reference. L of Z ispreferably an ethyl, butyl, hexyl, octyl or benzyl group.Polycarbonates, polyarylates and the poly(alkylene oxide) blockcopolymers thereof having pendent free carboxylic acid groups can alsobe prepared by the palladium-catalyzed hydrogenolysis of thecorresponding polymers with benzyl esters prepared as described in theearlier-referenced U.S. patent application Ser. No. 09/056,050. Thecatalytic hydrogenolysis may be performed as described in thisProvisional Patent Application, as well.

Polyarylates and polycarbonates, alone, or as segments within apoly(alkylene oxide) block copolymer, may be homopolymers with eachdihydroxy monomeric subunit having an iodine or a bromine atom. Thepolymers of the present invention also include copolymers of the samepolymer units with dihydroxy monomers that are iodine- and bromine-free.One can vary within the polymers the molar ratios of the monomericsubunits having bromine- and iodine atoms and the monomeric subunitsthat are bromine- and iodine-free.

Polymers in accordance with the present invention thus includehomopolymers of a repeating unit having at least one iodine or bromineatom. Such homopolymers have the structure of Formulae VIII and VIIIa inwhich f and g are both zero.

Polymers in accordance with the present invention thus also includecopolymers having monomeric repeating units that are bromine- andiodine-free. Such copolymers have the structure of Formulae VIII orVIIIa in which f is zero and g is a number greater than zero but lessthan one. In copolymers in accordance with the present invention, g ispreferably between about 0.25 and about 0.75.

In the preferred homopolymers and copolymers of Formula VIII, R₉ has thestructure of Formula II and R₁₂ has the structure of Formula V. Thepreferred species thereof are the same as described above with respectto Formula II and Formula V.

When A of Formulae VIII and VIIIa is:

the polymers of the present invention are polycarbonates. When f iszero, the iodine- and bromine-substituted polycarbonate homopolymers andcopolymers of the present invention may be prepared by the methoddescribed by U.S. Pat. No. 5,099,060 and by U.S. patent application Ser.No. 08/884,108, filed Jun. 27, 1997, the disclosures of both of whichare also incorporated herein by reference. The described method isessentially the conventional method for polymerizing dihydroxy monomersinto polycarbonates. Suitable processes, associated catalysts andsolvents are known in the art and are taught in Schnell, Chemistry andPhysics of Polycarbonates, (Interscience, New York 1964), the teachingsof which are incorporated herein by reference.

The polycarbonate homopolymers and copolymers in accordance with thepresent invention in which f=0 have weight-average molecular weightsranging between about 20,000 to about 400,000 daltons, and preferablyabout 100,000 daltons, measured by gel permeation chromatography (GPC)relative to polystyrene standards without further correction.

When A of Formulae VIII and VIIIa is:

the polymers of the present invention are polyarylates. The iodine- andbromine-substituted polyarylate homopolymers and copolymers of thepresent invention may-be prepared by the method described by U.S. Pat.No. 5,216,115, in which dihydroxy monomers are reacted with aliphatic oraromatic dicarboxylic acids in a carbodiimide mediated directpolyesterification using 4-(dimethylamino)pyridinium-p-toluene sulfonate(DPTS) as a catalyst to form aliphatic or aromatic polyarylates. Thedisclosure of this patent is also incorporated herein by reference. Itshould be noted that R₈ should not be substituted with functional groupsthat would cross-react.

Dicarboxylic acids from which the polyarylates materials of the presentinvention may be polymerized have the structure of Formula X:

in which, for the aliphatic polyarylates, R₈ is selected from saturatedand unsaturated, substituted and unsubstituted alkyl groups containingup to 18 carbon atoms, and preferably from 4 to 12 carbon atoms. Foraromatic polyarylates, R₈ is selected from aryl and alkylaryl groupscontaining up to 18 carbon atoms, but preferably from 8 to 14 carbonatoms. Again, R₈ should not be substituted with functional groups thatwould cross-react.

R₈ is even more preferably selected so that the dicarboxylic acids fromwhich the polyarylate starting materials are polymerized are eitherimportant naturally-occurring metabolites or highly biocompatiblecompounds. Preferred aliphatic dicarboxylic acids therefore include theintermediate dicarboxylic acids of the cellular respiration pathwayknown as the Krebs Cycle. These dicarboxylic acids includealpha-ketoglutaric acid, succinic acid, fumaric acid, maleic acid andoxalacetic acid. Other preferred biocompatible aliphatic dicarboxylicacids include sebacic acid, adipic acid, oxalic acid, malonic acid,glutaric acid, pimelic acid, suberic acid and azelaic acid. Among thepreferred aromatic dicarboxylic acids are terephthalic acid, isophthalicacid and bis(p-carboxyphenoxy) alkanes such as bis(p-carboxyphenoxy)propane. Stated another way, R₈ is more preferably a moiety selectedfrom —CH₂—C(═O)—, —CH₂—CH₂—C(═O)—, —CH═CH— and (—CH₂—)_(z), wherein z isan integer between two and eight, inclusive.

Iodine- and bromine-substituted polyarylate homopolymers and copolymersin accordance with the present invention have weight average molecularweights between about 20,000 and about 400,000 daltons, and preferablyabout 100,000 daltons, measured by GPC relative to polystyrene standardswithout further correction.

Iodine- and bromine-substituted polycarbonates and polyarylates inaccordance with the present invention also include random blockcopolymers with a poly(alkylene oxide) with the structure of FormulaeVIII or VIIIa, wherein f is greater than zero but less than one. Thevariable species, and the preferred embodiments thereof, are the same asdescribed above with respect to formulae VIII and VIIIa, except that fis no longer zero and the value for g is less than one, and g may or maynot be greater than zero.

The molar fraction of alkylene oxide in the block copolymer, f, rangesbetween about 0.01 and about 0.99. For preferred block copolymers, R₇ isethylene, k is between about 20 and about 200, and the molar fraction ofalkylene oxide in the block copolymer, f, preferably ranges betweenabout 0.05 and about 0.75. R₇ may also represent two or more differentalkylene groups within a polymer.

The block copolymers of the present invention may be prepared by themethod described by U.S. Pat. No. 5,658,995, the disclosure of which isalso incorporated herein by reference. The block copolymers haveweight-average molecular weights between about 20,000 and about 400,000daltons, and preferably about 100,000 daltons. The number-averagemolecular weights of the block copolymers are preferably above about50,000 daltons. Molecular weight determinations are measured by GPCrelative to PEG standards without further correction.

For homopolymers and copolymers in accordance with the present inventionhaving pendent carboxylic acid amide or ester groups, the amide or estergroup can be an amide or ester derivative of a biologically orpharmaceutically active compound covalently thereto. The covalent bondis by means of an amide bond when in the underivatized biologically orpharmaceutically active compound a primary or secondary amine is presentat the position of the amide bond in the derivative. The covalent bondis by means of an ester bond when in the underivatized biologically orpharmaceutically active compound a primary hydroxyl is present at theposition of the ester bond in the derivative. The biologically orpharmaceutically active compounds may also be derivatized at a ketone,aldehyde or carboxylic acid group with a linkage moiety such as thelinkage moiety R₃ of Formula IIIa, which is covalently bonded to thecopolymer or diphenol by means of an amide or ester bond.

Detailed chemical procedures for the attachment of various drugs andligands to polymer bound free carboxylic acid groups have been describedin the literature. See, for example, U.S. Pat. Nos. 5,219,564 and5,660,822; Nathan et al., Bio. Cong. Chem., 4, 54-62 (1993) and Nathan,Macromolecules, 25, 44-76 (1992). The disclosures of both patents inboth journal articles are incorporated herein by reference. Thesepublications disclose procedures by which polymers having pendent freecarboxylic acid group are reacted with moieties having reactivefunctional groups, or that are derivatized to contain active functionalgroups to form a polymer conjugate.

The order of reaction can also be reversed. The moiety may first beattached to a monomer having a pendent free carboxylic acid group, whichis then polymerized to form a polymer in which 100% of the pendent freecarboxylic acid groups have moieties attached thereto.

When a polymer having pendent free carboxylic acid groups is firstpolymerized and then reacted with a biologically or pharmaceuticallyactive compound or derivative thereof to form a polymer conjugate notall of the pendent free carboxylic acid groups will have a biologicallyor pharmaceutically active compound covalently attached thereto.Typically, a conjugate is formed in which biologically orpharmaceutically active compounds attach to at least about 25% of thependent free carboxylic acid groups.

Examples of biologically or pharmaceutically active compounds suitablefor use with the present invention include acyclovir, cephradine,malphalen, procaine, ephedrine, adriarnycin, daunomycin, plumbagin,atropine, quinine, digoxin, quinidine, biologically active peptides,chlorin e₆, cephradine, cephalothin, proline and proline analogs such ascis-hydroxy-L-proline, melphalan, penicillin V, aspirin, nicotinic acid,chemodeoxycholic acid, chlorambucil, and the like. Biologically activecompounds, for purposes of the present invention are additionallydefined as including cell attachment mediators, biologically activeligand and the like. The compounds are covalently bonded to thepolycarbonate or polyarylate copolymer by methods well understood bythose of ordinary skill in the art. Drug delivery compounds may also beformed by physically blending the biologically or pharmaceuticallyactive compound to be delivered with the polymers of the presentinvention. Either way, the polymers of the present invention provide ameans by which drug delivery may be monitored using x-ray imagingwithout having to employ a filler material to provide x-ray contrast.

For purposes of the present invention, the alkyl ester and amide groupswithin Z are also defined as including crosslinking moieties, such asmolecules with double bonds (e.g., acrylic acid derivatives), which canbe attached to the pendent carboxylic acid groups for crosslinking toincrease the strength of the polymers.

As noted above, the polymers of the present invention are iodine orbromine substituted at selected repeating subunits. For the purposes ofthe present invention, homopolymers (Formula VIII or VIIIa, x=0) aredefined as containing an iodine or bromine at each subunit. Thesehomopolymers can be polycarbonates or polyarylates which may containpolyalkylene oxide blocks. The homopolymers are best described as new,radio-opaque polymers that may have a number of pharmacological andbiological activities. Likewise, for the purposes of the presentinvention, copolymers (Formula VIII or VIIIa, 0<x<1) are defined ascontaining iodine or bromine at some of the diphenolic subunits. Thesecopolymers can be polycarbonates or polyarylates, which also may containpolyalkylene oxide blocks.

The invention described herein also includes various pharmaceuticaldosage forms containing the polymers of the present invention. Thepharmaceutical dosage forms include those recognized conventionally,e.g. tablets, capsules, oral liquids and solutions, drops, parenteralsolutions and suspensions, emulsions, oral powders, inhalable solutionsor powders, aerosols, topical solutions, suspensions, emulsions, creams,lotions, ointments, transdermal liquids and the like.

The pharmaceutical dosage forms may include one or more pharmaceuticallyacceptable carriers. Such materials are non-toxic to the recipients atthe dosages and concentrations employed, and include diluents,solubilizers, lubricants, suspending agents, encapsulating materials,penetration enhancers, solvents, emollients, thickeners, dispersants,buffers such as phosphate, citrate, acetate and other organic acidsalts, anti-oxidants such as ascorbic acid, preservatives, low molecularweight (less than about 10 residues) peptides such as polyarginine,proteins such as serum albumin, gelatin, or immunoglobulins, otherhydrophilic polymers such as poly(vinylpyrrolidinone), amino acids suchas glycine, glutamic acid, aspartic acid, or arginine, monosaccharides,disaccharides, and other carbohydrates, including cellulose or itsderivatives, glucose, mannose, or dextrines, chelating agents such asEDTA, sugar alcohols such as mannitol or sorbitol, counterions such assodium and/or nonionic surfactants such as tween, pluronics or PEG.

The drug-polymer compositions of the present invention, regardless ofwhether they are in the form of polymer-drug conjugates or physicaladmixtures of polymer and drug, are suitable for applications wherelocalized drug delivery is desired, as well as in situations where asystemic delivery is desired. The polymer-drug conjugates and physicaladmixtures may be implanted in the body of a patient in need thereof, byprocedures that are essentially conventional and well-known to those ofordinary skill in the art.

Hydrolytically stable conjugates are utilized when the biological orpharmaceutical compound is active in conjugated form. Hydrolyzableconjugates are utilized when the biological or pharmaceutical compoundis inactive in conjugated form. The properties of the poly(alkyleneoxide) dominate the polymer and conjugate thereof Conjugates of thepolymers of the present invention with proline and proline analogs suchas cis-hydroxy-L-proline may be used in the treatment methods disclosedin U.S. Pat. No. 5,660,822. The disclosure of this patent isincorporated herein by reference.

Physical admixtures of drug and polymer are prepared using conventionaltechniques well-known to those of ordinary skill in the art. For thisdrug delivery embodiment, it is not essential that the polymer havependent free carboxylic acid groups.

The drug components to be incorporated in the polymer-drug conjugatesand physical admixtures of this invention may be provided in aphysiologically acceptable carrier, excipient stabilizer, etc., and maybe provided in sustained release or timed release formulationssupplemental to the polymeric formulation prepared in this invention.The carriers and diluents listed above for aqueous dispersions are alsosuitable for use with the polymer-drug conjugates and physicaladmixtures.

Subjects in need of treatment, typically mammalian, using thepolymer-drug combinations of this invention, can be administered drugdosages that will provide optimal efficacy. The dose and method ofadministration will vary from subject to subject and be dependent uponsuch factors as the type of mammal being treated, its sex, weight, diet,concurrent medication, overall clinical condition, the particularcompounds employed, the specific use for which these compounds areemployed, and other factors which those skilled in the medical arts willrecognize. The polymer-drug combinations of this invention may beprepared for storage under conditions suitable for the preservation ofdrug activity as well as maintaining the integrity of the polymers, andare typically suitable for storage at ambient or refrigeratedtemperatures.

Aerosol preparations are typically suitable for nasal or oralinhalation, and may be in powder or solution form, in combination with acompressed gas, typically compressed air. Additionally, aerosols may beused topically. In general, topical preparations may be formulated toenable one to apply the appropriate dosage to the affected area oncedaily, and up to three to four times daily, as appropriate.

Depending upon the particular compound selected, transdermal deliverymay be an option, providing a relatively steady delivery of the drug,which is preferred in some circumstances Transdermal delivery typicallyinvolves the use of a compound in solution, with an alcoholic vehicle,optionally a penetration enhancer, such as a surfactant, and otheroptional ingredients. Matrix and reservoir type transdermal deliverysystems are examples of suitable transdermal systems. Transdermaldelivery differs from conventional topical treatment in that the dosageform delivers a systemic dose of the drug to the patient.

The polymer-drug formulations of this invention may also be administeredin the form of liposome delivery systems, such as small unilamellarvesicles, large unilamellar vesicles and multilamellar vesicles.Liposomes may be used in any of the appropriate routes of administrationdescribed herein. For example, liposomes may be formulated that can beadministered orally, parenterally, transdermally, or via inhalation.Drug toxicity could thus be reduced by selective drug delivery to theaffected site. For example, if the drug is liposome encapsulated, and isinjected intravenously, the liposomes used are taken up by vascularcells and locally high concentrations of the drug could be released overtime within the blood vessel wall, resulting in improved drug action.The liposome encapsulated drugs are preferably administeredparenterally, and particularly, by intravenous injection.

Liposomes may be targeted to a particular site for drug release. Thiswould obviate excessive dosages that are often necessary to provide atherapeutically usefull dosage of a drug at the site of activity, andconsequently, the toxicity and side effects associated with higherdosages.

The drugs incorporated into the polymers of this invention may desirablyfurther incorporate agents to facilitate their delivery systemically tothe desired drug target, as long as the delivery agent meets the sameeligibility criteria as the drugs described above. The active drugs tobe delivered may in this fashion be incorporated with antibodies,antibody fragments, growth factors, hormones, or other targetingmoieties, to which the drug molecules are coupled. The polymer-drugcombinations of this invention may be formed into shaped particles, suchas valves, stents, tubing, prostheses, and the like.

Therapeutically effective dosages may be determined by either in vitroor in vivo methods. For each particular compound of the presentinvention, individual determinations may be made to determine theoptimal dosage required. The range of therapeutically effective dosageswill naturally be influenced by the route of administration, thetherapeutic objectives, and the condition of the patient. For thevarious suitable routes of administration, the absorption efficiencymust be individually determined for each drug by methods well known inpharmacology. Accordingly, it may be necessary for the therapist totiter the dosage and modify the route of administration as required toobtain the optimal therapeutic effect. The determination of effectivedosage levels, that is, the dosage levels necessary to achieve thedesired result, will be within the ambit of one skilled in the art.Typically, applications of compound are commenced at lower dosagelevels, with dosage levels being increased until the desired effect isachieved. The release rate of the drug from the formulations of thisinvention are also varied within the routine skill in the art todetermine an advantageous profile, depending on the therapeuticconditions to be treated.

A typical dosage might range from about 0.001 mg/k/g to about 1,000mg/k/g, preferably from about 0.01 mg/k/g to about 100 mg/k/g, and morepreferably from about 0.10 mg/k/g to about 20 mg/k/g. Advantageously,the compounds of this invention may be administered several times daily,and other dosage regimens may also be useful.

In practicing the methods of this invention, the polymer-drugcombinations may be used alone or in combination with other therapeuticor diagnostic agents. The compounds of this invention can be utilized invivo, ordinarily in mammals such as primates such as humans, sheep,horses, cattle, pigs, dogs, cats, rats and mice, or in vitro.

The polymers of the present invention also find application in areaswhere both solid materials and solvent-soluble materials are commonlyemployed. Such applications include polymeric scaffolds in tissueengineering applications and medical implant applications, including theuse of the polymers of the present invention to form shaped articlessuch as vascular grafts and stents, bone plates, sutures, implantablesensors, scaffolds for tissue regeneration, and other therapeutic agentparticles that decompose harmlessly within a known period of time.Shaped particles can be formed by conventional techniques such asextrusion, compression molding, injection molding, solvent casting, spincasting, and the like.

The polymers of the present invention are soluble in both water andorganic media. Accordingly, they can be processed by solvent castingtechniques and are good film formers. The polymers of the presentinvention having pendent free carboxylic acid groups can also be used toinfluence the interactions with cells, as disclosed in theabove-referenced International Publication No. 98/36013.

The incorporation of polyalkylene oxide blocks decreases theadhesiveness of the polymeric surfaces. Polymers for which f is greaterthan 5 mole percent according to Formulae VIII or VIIIa are resistant tocell attachment and may be useful as non-thrombogenic coatings onsurfaces in contact with blood. These polymers also resist bacterialadhesion. The polymers thus can be formed as a coating on the surface ofmedical devices by conventional dipping or spray coating techniques toprevent the formation of blood clots or the adhesion of bacteria on thesurface of the device.

The film forming properties of polymers with poly(alkylene oxide) can beadvantageously combined with the resistance to cell attachment toprovide films for use as barriers for the prevention of surgicaladhesions. A coating of the polymer of the present invention may also beapplied to injured tissue to provide a surgical adhesion barrier.

The polymers of the present invention can find application in areaswhere both structural solid materials and water-soluble materials arecommonly employed. Such applications include polymeric scaffolds intissue engineering applications and medical implant applications,including the use of the polycarbonates and polyarylates of the presentinvention to form shaped articles such as vascular grafts and stents,bone plates, sutures, implantable sensors, barriers for surgicaladhesion prevention, implantable drug delivery devices, scaffolds fortissue regeneration, and other therapeutic agent articles that decomposeharmlessly within a known period of time.

INDUSTRIAL APPLICABILITY

Shaped articles may be prepared from the polymers of the presentinvention for medical implant and drug delivery applications. Thearticles are radio-opaque and may be monitored using x-ray imagingwithout having to employ a filler material to provide x-ray contrast.

The following non-limiting examples set forth hereinbelow illustratecertain aspects of the invention. All parts and percentages are by molepercent unless otherwise noted and all temperatures are in degreesCelsius. All solvents were HPLC grade. All other reagents were ofanalytical grade and were used as received.

The following Examples illustrate the preparation of3-(3-iodo-4-hydroxyphenyl)propanoic acid-tyrosine ethyl ester (DITE),and its incorporation into a variety of polymer structures. Since aniodine is present is the structure of DITE, the materials illustrated inthe following Examples are radio-opaque.

EXAMPLE 1 Synthesis of DITE

DITE (3-(3-iodo-4-hydroxyphenyl)propanoic acid-tyrosine ethyl ester) isa bisphenol carrying one iodine atom at position 3 of one of the twophenolic rings. This bifunctional molecule can be polymerized asillustrated in the subsequent Examples. This Example describes themethod used to introduce the iodine atom in the aromatic ring(4-hydroxyphenyl)propionic acid, and the coupling of this iodinatedderivative with tyrosine ethyl ester in order to obtain DITE.

Preparation of solution (a): to a 250 mL Erlenmeyer flask were added 100mL of distilled water, 24 g of potassium iodide, and 25 g of iodine. Themixture was stirred overnight until all solids dissolved.

Preparation of solution (b): 16.6 g (0.1 mole) of DAT were placed in a3-necked Morton-type round bottom flask, equipped with an overhead mixerand a 125 mL addition funnel. 140 mL of 40% trimethylamine solution inwaterwere added, and the mixture was stirred until a clear solution wasobtained.

Solution (a) was placed in the addition funnel, and added dropwise tosolution (b) while vigorously stirring. Addition of each drop ofsolution (a) imparted a brown color to the reaction mixture. The rate ofaddition was such that all the color disappeared before the next dropwas added. Stirring was continued for one hour after the last addition,the 50 mL of sodium thiosulfate 0.1 M were added to the reaction vessel.The same solution was also used to wash the addition funnel.

37% HCl was added dropwise with vigorous mixing until the solution wasslightly acidic to litmus, and a solid formed. The mixture wasconcentrated to half its volume by rotary evaporation, and then it wasextracted with ether. The organic phase was dried over magnesiumsulfate, and decolorized using animal charcoal. The slurry was thenfiltered through a small layer of silica gel, and evaporated to dryness.The white solid was recrystallized twice in toluene, recovered byfiltration, dried under a stream of nitrogen, and then under highvacuum.

Characterization: DSC analysis showed a melting point range of 109-111°C. ¹H-NMR (DMSO) of the product showed the following peaks (ppm): 2.5(t, 2H), 2.7 (t, 2H), 6.8 (d, 2H), 7.06 (d, 2H), 10.08 (s, 1H), 12.05(s, 1H). Reverse-phase HPLC showed 3.8% DAT (the starting material), and1.4% of diiodinated product.

Step 2: Preparation of 3-(3-iodo-4-hydroxyphenyl)propionic acid-tyrosineethyl ester (DITE)

To a 250 mL 3-necked round bottomed flask equipped with an overheadstirrer were added 17.0 g (0.0582 moles) of DIAT, 12-25 g (0.0585 moles)or tyrosine ethyl ester, and 25 mL of NMP. The mixture was stirred untila clear solution was obtained. The flask was cooled in an ice-waterbath, the 11.84 g (0.0619 moles) of EDCI HCl were added in one portion,followed by 15 mL of NMP. The cooling bath was removed after 2.5 hours,and the reaction was allowed to continue overnight at room temperature.71 mL of ethyl acetate were added, and stirring was maintained for 15more minutes. The crude was then transferred into a 500 mL separatoryfunnel, and extracted once with 75 mL of brine, then with two aliquots(75 and 35 mL) of 3% NaHCO3/14% NaCl, followed by 35 mL aliquots of 0.4MHCl/14% NaCl, and finally with brine. The organic phase was dried overmagnesium sulfate and treated with activated carbon, filtered andconcentrated to a thick syrup, which crystallized into a solid massafter a few hours. The product was triturated in methylene chlorideusing mechanical stirring, then it was recovered by filtration and driedunder a nitrogen stream followed by high vacuum.

Characterization: DSC analysis showed a melting point range of 110-113°C. ¹H-NMR (DMSO) showed the following peaks (ppm): 1.1 (t, 3H), 2.35 (t,2H), 2.65 (m, 2H), 2.85 (m, 2H), 4.05 (q, 2H), 4.35 (m, 1H),6.65/6-75/6.95 (m, 6H), 7.5 (s, 1H), 8.25 (d, 1H), 9.25 (s, 1H), 10.05(s, 1H). Reverse-phase HPLC showed 2.2% of DTE (the non-iodinatedmonomer), and no diiodinated product.

EXAMPLE 2 Poly(DITE carbonate) by Solution Polymerization

This material is the polycarbonate obtained by reacting DITE, obtainedin Example 1, and phosgene.

Polymerization of DITE with Phosgene

A 250 mL 3-necked flask equipped with a mechanical stirrer and anaddition funnel was purged with nitrogen for 15 minutes. 7.62 g (15.8moles) of DITE were added to the flask followed by 39 mL methylenechloride and 4.79 mL distilled pyridine. The mixture was stirred until aclear solution was obtained, then it was chilled in an ice-water bath.9.8 mL of 20% phosgene solution in toluene were placed in the additionfunnel and added to the reaction flask at a constant rate so that theentire addition was complete in 1.5 hours. The mixture was stirred forone more hour, then it was diluted with 200 mL THF, and the polymer wasprecipitated by dropping the solution in a large excess of ether througha filter funnel. The precipitated polymer was washed with ether,transferred to an evaporating dish, and dried overnight under a steam ofnitrogen. It was redissolved in THF, and precipitated again in awater/ice mixture, using a high-speed blender. The product was thendried under a stream of nitrogen, followed by high vacuum at 40° C.

Characterization: The composition of the product was confirmed byElemental Analysis: % C=50.60 (theor: 49.52%); % H=4.21 (theor: 3.96%);% N=2.65 (theor: 2.75%); % I—24.01 (theor: 24.92%). A Mw of 104K with apolydispersity of 1.8 was determined by GPC in THF vs. polystyrenestandards. DSC showed a Tg of 103.8° C. ¹H-NMR (DMSO-D₆) showed thefollowing peaks (ppm): 1.1 (t, 3H), 2.4 (broad, 2H), 2.75 (broad, 2H),3.0 (broad, 2H), 4.05 (q, 2H), 4.45 (m, 1H), 7.3 (m, 6H), 7.8 (s, 1H),8.4 (d, 1H).

EXAMPLE 3 Poly(DITE-co-5% PEG1K Carbonate) by Solution Polymerization

In this Example, 5 mole % of PEG1000 was copolymerized with DITE throughphosgenation by means of a solution polymerization technique similar tothat described in Example 2. The resulting material is a randompolycarbonate.

Copolymerization of DITE and PEG1000

A 100 mL 3-necked round bottomed flask equipped with an addition funneland an overhead stirrer was purged with nitrogen for 30 minutes. Theflask was charged with 5 g (10.33 mmoles) of DITE, and 0.545 g (0.55mmoles) of PEG1000, then 23 mL of methylene chloride and 3.3 mL ofpyridine were added, and the mixture was stirred until a colorless,clear solution resulted. The flask was cooled in an ice-water bath, and6.4 mL of 20% phosgene solution in toluene were-added dropwise over aperiod of 90 minutes from the addition funnel. The mixture was dilutedwith 90 mL of THE, and stirred for one more hour. The product wasisolated by precipitation in 800 mL of ethyl ether, and dried under astream of nitrogen followed by high vacuum.

Characterization: A Mw of 75,500 with a polydispersity of 1.8 wasdetermined by GPC vs. polystyrene standards, with THF as the mobilephase. DSC showed Tg of 70° C. ¹H-NMR (CDCl₃) showed the following peaks(ppm): 1.2 (t, 3H), 2.45 (broad, 2H), 2.8 (broad, 2H), 2.03 (broad, 2H),3.65 (s, 4.5 PEG protons), 4.15 (q, 2H), 4.85 (m, 1H), 6.05 (broad, 1H),7.05/7.15 (m, 6H), 7.2 (s, 1H). The peaks at 7.05/7.15, and at 7.2 arediagnostic for the presence of the iodine atom on the aromatic system ofthe polymer. Broad-Band Decoupled ¹³C NMR (CDCl₃) showed all theexpected peaks, and in particular that of the aromatic carbon bearingthe iodine (90 ppm).

EXAMPLE 4 Poly(DITE Adipate) by Solution Polymerization

This material is an alternating copolymer of the iodine-containingdiphenol DITE, and adipic acid, an aliphatic diacid. The monomers arelinked through an ester bond to form a polyarylate backbone. ThisExample illustrates the preparation of this copolymer by means of acondensation reaction promoted by the coupling agentdiisopropylcarbodiimnide (DIPC).

Copolymerization of DITE and Adipic Acid

A 100 mL round bottomed flask equipped with an overhead stirrer waspurged with nitrogen for one hour, and then charged with 4.349 g (9.0mmoles) of DITE, 1.315 g (9.0 mmoles) of adipic acid, 1.06 ofdimethylaminopyridinium p-toluene sulfonate (2.5 mmoles), and 68 mL ofmethylene chloride. The mixture was stirred for five minutes, then 4.2mL (27 mmoles) of DIPC were added in one portion. Stirring was continuedovernight at room temperature, then the reaction crude was filtered, andthe polymer was precipitated in 600 mL of chilled isopropanol in ahigh-speed blender, and isolated by filtration. The polymer was washedin the high-speed blender with 600 mL of chilled isopropanol, and the600 mL of a water/ice mixture. The product was dried overnight under astream of nitrogen, and then was transferred to high vacuum at roomtemperature.

Characterization: A Mw of 67,100 with a polydispersity of 1.9 wasdetermined by GPC vs. polystyrene standards, with THF as the mobilephase. DSC showed a Tg of 66.5° C. ¹H-NMR (DMSO-D₆) showed the followingpeaks (ppm): 1.1 (t, 3H), 1.75 (broad, 4H), 2.4 (broad, 2H), 2.7 (broad,6H), 2.95 (broad, 2H), 405 (q, 2H0, 4.45 (m, 1H), 7.05/7.15 (m, 6H), 7.7(s, 1H), 8.4 (d, 1H).

EXAMPLE 6 Fabrication and Implantation of Radio-Opaque Rods

Iodine-containing, radio-opaque polymers can be blended with nonradio-opaque materials in order to fabricate implantable devices thatare x-ray detectable. This example illustrates the preparation of blendsof poly(DTE carbonate) and poly(DITE carbonate) in three differentratios, their fabrication into rods, and their implantation into ananimal model.

Preparation of Radio-opaque Polymer Blends

Three blends with different ratios of poly(DTE carbonate) (Mw=103 K) topoly(DITE carbonate) (Mw=106 K) were prepared. The weight ratios were90/10, 75/25 and 50/50. In each case, the polymers were co-dissolved inmethylene chloride, and the mixture was precipitated in ether.

Fabrication and Implantation of Radio-opaque Rods

Uniform rods of 10 mm length, 2 mm diameter were obtained by meltextrusion at 180° C. The rods were implanted in rabbit long bones, andsites of implantation were x-rayed in order to confirm the radio-opacityof the devices. Radio-opacity increased with increasing content ofpoly(DITE carbonate).

The foregoing examples illustrate that radio opacity may be obtained byBr and I ring-substitution of essentially any aromatic ring-containingpolymer. These examples, and the foregoing description of the preferredembodiment, should be taken as illustrating, rather than as limiting,the present invention as defined by the claims. As will be readilyappreciated, numerous variations and combinations of the features setforth above can be utilized without departing from the present inventionas set forth in the claims. Such variations are not regarded as adeparture from the spirit and scope of the invention, and all suchmodifications are intended to be included within the scope of thefollowing claims.

1. A radio-opaque, biocompatible stent comprising a radio-opaque,biocompatible polymer.
 2. The radio-opaque, biocompatible stent of claim1 wherein said polymer comprises at least one repeating unit derivedfrom a dihydroxy monomer having at least one iodide or bromidesubstituent.
 3. The radio-opaque, biocompatible stent of claim 2 whereinsaid polymer comprises at least one repeating unit derived from aniodine-substituted dihydroxy monomer.
 4. The radio-opaque, biocompatiblestent of claim 2 wherein said polymer comprises at least one repeatingunit derived from a bromine-substituted dihydroxy monomer.
 5. Theradio-opaque, biocompatible stent of claim 2 wherein said dihydroxymonomer is an aromatic dihydroxy monomer ring-substituted with at leastone bromine or iodine atom.
 6. The radio-opaque, biocompatible stent ofclaim 5 wherein said aromatic dihydroxy monomer is a diphenol compoundsubstituted on at least one ring with at least one bromine or iodineatom.
 7. The radio-opaque, biocompatible stent of claim 1 wherein saidpolymer comprises one or more polymeric blocks selected from the groupconsisting of iodine-containing polyarylates, iodine-containingpolycarbonates, bromine-containing polyarylates, bromine-containingpolycarbonates, and combinations of two or more thereof.
 8. Theradio-opaque, biocompatible stent of claim 7 wherein said polymerfurther comprises one or more poly(alkylene oxide) blocks.
 9. Theradio-opaque, biocompatible stent of claim 1 wherein said stent isformed from said polymer.
 10. The radio-opaque, biocompatible stent ofclaim 9 wherein said stent is formed via extrusion, compression molding,injection molding, solvent casting, spin casting, or combinations of twoor more thereof.
 11. The radio-opaque, biocompatible stent of claim 1wherein said stent is coated with said polymer.